IGF1R Inhibition in Mammary Epithelia Promotes Canonical Wnt Signaling and Wnt1-Driven Tumors
| Autor: | Sain Shushanov, Teresa L. Wood, Lauren Rota, Derek LeRoith, Marcus E Shin, Lidia Albanito, Emily J. Gallagher, Corey Goyeneche, Deborah A Lazzarino |
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| Rok vydání: | 2014 |
| Předmět: |
Homeobox protein NANOG
Genetically modified mouse Cancer Research Pathology medicine.medical_specialty Lung Neoplasms Mice Transgenic Wnt1 Protein Biology Real-Time Polymerase Chain Reaction medicine.disease_cause Article Receptor IGF Type 1 Mice Mammary Glands Animal Growth factor receptor medicine Animals Progenitor cell Insulin-like growth factor 1 receptor Wnt signaling pathway Mammary Neoplasms Experimental Oncology Cancer research Female Signal transduction Carcinogenesis Signal Transduction |
| Zdroj: | Cancer Research. 74:5668-5679 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | Triple-negative breast cancer (TNBC) is an aggressive disease subtype that, unlike other subtypes, lacks an effective targeted therapy. Inhibitors of the insulin-like growth factor receptor (IGF1R) have been considered for use in treating TNBC. Here, we provide genetic evidence that IGF1R inhibition promotes development of Wnt1-mediated murine mammary tumors that offer a model of TNBC. We found that in a double transgenic mouse model carrying activated Wnt1 and mutant Igf1r, a reduction in IGF1R signaling reduced tumor latency and promoted more aggressive phenotypes. These tumors displayed a squamous phenotype with increased expression of keratins 5/6 and β-catenin. Notably, cell lineage analyses revealed an increase in basal (CD29hi/CD24+) and luminal (CD24+/CD61+/CD29lo) progenitor cell populations, along with increased Nanog expression and decreased Elf5 expression. In these doubly transgenic mice, lung metastases developed with characteristics of the primary tumors, unlike MMTV-Wnt1 mice. Mechanistic investigations showed that pharmacologic inhibition of the IGF1R in vitro was sufficient to increase the tumorsphere-forming efficiency ofMMTV-Wnt1 tumor cells. Tumors from doubly transgenic mice also exhibited an increase in the expression ratio of the IGF-II-sensitive, A isoform of the insulin receptor versus the IR-B isoform, which when stimulated in vitro resulted in enhanced expression of β-catenin. Overall, our results revealed that in Wnt-driven tumors, an attenuation of IGF1R signaling accelerates tumorigenesis and promotes more aggressive phenotypes with potential implications for understanding TNBC pathobiology and treatment. Cancer Res; 74(19); 5668–79. ©2014 AACR. |
| Databáze: | OpenAIRE |
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